Neurocognitive changes with breast cancer and its treatment are significant symptoms in the majority of women with this disease. Unfortunately, very little is known about the mechanisms that underlie these neurocognitive changes, which in turn limits the development of effective treatments and prevention strategies. Evidence supports that DNA methylation impacts cognitive function (CF) and brain health (BH), exercise impacts DNA methylation, and exercise impacts CF and BH. Although investigating DNA methylation patterns has potential to uncover novel biological underpinnings to help us understand neurocognitive changes within the context of breast cancer and its treatment, no DNA methylation study has evaluated the interrelationships among CF, BH and exercise within the context of breast cancer and its treatment. The purpose of the proposed study is to examine the dynamic DNA methylome to identify genes and biological pathways that are involved with CF and BH within the context of breast cancer and its treatment. This project capitalizes on data and samples generated through an ongoing project that involves women newly diagnosed with early stage breast cancer who will receive aromatase inhibitor (AI) therapy and randomizes them to an exercise intervention or usual care. Because breast cancer and AI therapy impact CF and BH in a negative manner and exercise impacts CF and BH in a positive manner; this project offers an exemplar, unique opportunity to identify biological mechanisms involved in CF and BH within the context of breast cancer and its treatment. Phenotype data for CF will focus on cognitive domains that deteriorate with AI therapy including attention, working memory, and executive function, and brain health will be measured using neuroimaging including regional gray matter volume, white matter architecture, and functional dynamics of the brain. Cognitive function may be mediated by commonly occurring symptoms therefore this study will include evaluating fatigue, sleep problems, depression, and anxiety for their potential to mediate or moderate the impact of DNA methylation on CF and BH. Whole genome DNA methylation data will be generated for all women at two time points: at enrollment when all women will be pre AI therapy and not yet randomized and post 6 months intervention for those randomized to the exercise intervention and usual care. This allows us to address mechanisms for CF and BH within the context of breast cancer prior to therapy, within the context of AI therapy, and within the context of an exercise intervention. An additional aim of this project will replicate significant findings using data and DNA samples from a project that recruits older healthy individuals, randomizes them to an identical exercise intervention, similarly measures CF and BH phenotypes, and collects biological samples at the same time points. Findings from this project have the potential to inform evidence based, mechanistically driven therapeutic interventions to mitigate the negative consequences of cancer and its treatment.